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Abstract

Over the past several decades, the rate of pulmonary nontuberculous my-
cobacterial (PNTM) disease has been increasing. PNTM patients gener-
ally consist of lean and tall women presenting with symptoms in the sixth
decade of life. They have a de nitive morphophenotype, but no consistent
immunological abnormalities despite extensive investigation. I hypothesized
that respiratory epithelial dysfunction might play a critical role in PNTM
disease predisposition because diseases with defects of mucociliary transport have high rates of PNTM disease that increase with age, suggesting a
direct connection between airway epithelial function and PNTM disease.
I found that PNTM patients have a distinct respiratory epithelial phenotype ex vivo and decreased nasal nitric oxide levels in vivo. The PNTM ex
vivo phenotype consists of an abnormally low resting ciliary beat frequency
(CBF) and abnormal CBF response to toll-like receptor (TLR) agonists.
The depressed baseline CBF response in PNTM patient cells can be normalized ex vivo by augmenting the nitric oxide-cyclic guanosine monophosphate pathway without appreciable e ect on CBF in healthy controls. In
healthy controls, bacterial TLR agonists increase CBF and viral TLR agonists decrease CBF. In PNTM patients these responses are impaired and
are not normalized with the normalization of the resting CBF rate.
Inhibitor-induced disruption of signalling pathways associated with CBF
regulation demonstrated that the majority of the CBF response to TLR
agonists involves the PI-3K pathway and PKC. Inhibition of the PI-3K
pathway (PI-3K , Akt1, and PDK1) closely mimicked the ex vivo phenotype seen in PNTM patient respiratory epithelia.
These data identify a novel aspect of PNTM disease with in vivo and ex vivo
correlates that suggest that PNTM infection is associated with abnormal
function at both the CBF and TLR response levels. This phenotype is
novel, reproducible, and provide a foundation with which to determine the
genetic basis of PNTM infection.